Alzheimer’s may 'seed' itself like mad cow disease19:00 21 September 2006 NewScientist.com news service Roxanne Khamsi Proteins taken from the brains of Alzheimer’s patients and injected into the brains of genetically engineered mice trigger Alzheimer’s-like lesions in the mouse brains, researchers report.The findings suggest that the malformed protein clumps associated with Alzheimer’s disease can “seed” themselves in a way reminiscent of the missfolded proteins in prion diseases such as “mad cow” disease.

The exact causes of Alzheimer’s remain a mystery, but it appears that beta-amyloid proteins contribute to the formation of disruptive plaques in the brain. The neurological damage accumulates over years, causing loss of memory, language and other crucial mental skills.

Experts studying how beta amyloid might promote plaque formation have speculated that this might happen in a process similar to that in prion diseases.

Infectious agentsPrion illnesses, such as mad cow disease, are special in that proteins apparently act as the infectious agents, rather than genetic material or a microorganism. In laboratory tests, animals that receive prion proteins develop brain plaques and eventually die as a result.

Previous experiments have shown that injections of brain extracts from Alzheimer’s patients can trigger brain plaque formation in marmoset monkeys and mice.

But it has not been clear whether the beta-amyloid proteins themselves are responsible for this effect, or some other component of the brain tissue, says Lary Walker at Emory University in Atlanta, Georgia, US.

To investigate this, Walker's team used "APP23 mice" – genetically engineered to carry the human gene with a mutation that causes the animals to develop plaques in old age.

Seed huntingWhen the young APP23 mice received brain extracts from either humans who had died with Alzheimer’s disease, or from older APP23 mice, the young mice developed brain plaques within weeks instead of the usual year.

Next, the team took brain extracts from old APP23 mice and exposed them to molecules that specifically bind and disable beta-amyloid proteins. When these treated extracts were injected into the brains of young mice, they did not cause the formation of plaques.

“For the first time we show that the likely seed is beta amyloid itself,” says Walker.

He notes that there is no evidence to suggest that beta amyloid alone can accelerate Alzheimer’s-like plaques in mice that are not genetically predisposed to the illness.

Walker adds that the evidence from the new experiment should encourage scientists to find out which forms of beta amyloid might promote plaque formation most aggressively in humans.

AApoAII amyloid fibrils have exhibited prion-like transmissibility in mouse senile amyloidosis. We have demonstrated that AApoAII is extremely active and can induce amyloidosis following doses less than 1 pg. We tested physical and chemical methods to disrupt AApoAII fibrils in vitro as determined by thioflavin T binding and electron microscopy (EM) as well as inactivating the transmissibility of AApoAII fibrils in vivo. Complete disruption of AApoAII fibrils was achieved by treatment with formic acid, 6 M guanidine hydrochloride, and autoclaving in an alkaline solution. Injection of these disrupted AApoAII fibrils did not induce amyloidosis in mice. Disaggregation with 6 M urea, autoclaving, and alkaline solution was incomplete, and injection of these AApoAII fibrils induced mild amyloidosis. Treatment with formalin, delipidation, freeze-thaw, and RNase did not have any major effect. A distinct correlation was obtained between the amounts of amyloid fibrils and the transmissibility of amyloid fibrils, thereby indicating the essential role of fibril conformation for transmission of amyloidosis. We also studied the inactivation of AApoAII fibrils by several organic compounds in vitro and in vivo.

AApoAII amyloidosis provides a valuable system for studying factors that may prevent transmission of amyloid disease as well as potential novel therapies.

http://www.fasebj.org/cgi/content/abstract/fj.05-4890fjev1

another transmissible protein amyloidosis? what does this implicate with Alzheimer's and TSE, if anything?.........TSS

CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

Dr McGovern From: Dr A Wight

Date: 5 January 1993

Copies: Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

1. CMO will wish to be aware that a meeting was held at DH yesterday,4 January, to discuss the above findings. It was chaired by ProfessorMurray (Chairman of the MRC Co-ordinating Committee on Research inthe Spongiform Encephalopathies in Man), and attended by relevantexperts in the fields of Neurology, Neuropathology, molecular biology,amyloid biochemistry, and the spongiform encephalopathies, and byrepresentatives of the MRC and AFRC.

ii) there were no immediate implications for the public health, and nofurther safeguards were thought to be necessary at present; and

iii) additional research was desirable, both epidemiological and at themolecular level. Possible avenues are being followed up by DHand the MRC, but the details will require further discussion.

93/01.05/4.1

http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

BSE101/1 0136

IN CONFIDENCE

5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC haverecognised the public sensitivity of these findings and intend to reportthem in theirproper context. This hopefully will avoid misunderstanding and possibledistortion bythe media to portray the results as having more greater significance thanthe findingsso far justify.

2. Using a highly unusual route of transmission (intra-cerebral injection)theresearchers have demonstrated the transmission of a pathological processfrom twocases one of severe Alzheimer's disease the other of Gerstmann-Strausslerdisease tomarmosets. However they have not demonstrated the transmission of eitherclinicalcondition as the "animals were behaving normally when killed'. As the reportemphasises the unanswered question is whether the disease condition wouldhaverevealed itself if the marmosets had lived longer. They are planning funherresearchto sec if the conditions, as opposed to the partial pathological process, istransmissible.

What are the implications for public health?

3. . The route of transmission is very specific and in the natural state ofthingshighly unusual. However it could be argued that the results reveal apotential risk,in that brain tissue from these two patients has been shown to transmit apathologicalprocess. Should therefore brain tissue from such cases be regarded aspotentiallyinfective? Pathologists, morticians, neuro surgeons and those assisting atneurosurgical procedures and others coming into contact with "raw" human braintissuecould in theory be at risk. However, on a priori grounds given the highlyspecificroute of transmission in these experiments that risk must be negligible ifthe usualprecautions for handling brain tissue are observed.

92/11.4/1-1

BSE101/1 0137

4. The other dimension to consider is the public reaction. To some extentthe GSScase demonstrates little more than the transmission of BSE to a pig byintra-cerebralinjection. If other prion diseases can be transmitted in this way it islittle surprise thatsome pathological findings observed m GSS were also transmissible to amarmoset.But the transmission of features of Alzheimer's pathology is a differentmatter, giventhe much greater frequency of this disease and raises the unansweredquestion whethersome cases are the result of a transmissible prion. The only tenable publicline willbe that "more research is required" before that hypothesis could beevaluated. Thepossibility on a transmissible prion remains open. In the meantime MRC needscarefully to consider the range and sequence of studies needed to followthrough fromthe preliminary observations in these two cases. Not a particularlycomfortablemessage, but until we know more about the causation of Alzheimer's diseasethe totalreassurance is not practical.